There is increasing evidence that a deficit in sensorimotor gating is a cardinal feature of the underlying pathophysiology of schizophrenia. One test commonly used to assess these deficits in sensorimotor gating is prepulse inhibition (PPI) of the acoustic startle reflex. Significant sex differences have been reported in schizophrenia and in PPI. The neuropeptide neurotensin (NT) is implicated in the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs and in regulation of PPI. Preliminary data demonstrated that there is both sex- and estrous cycle-related regulation of the rat NT system, and in the response of this system to antipsychotic drug administration. Demonstration that estrous cycle-related regulation of NT neurotransmission is involved in ovarian hormone regulation sensorimotor gating is the overall objective of this proposal. Hypotheses to be tested include the following: Are the alterations in PPI seen across the estrous cycle associated with changes in NT neurotransmission? Are antipsychotic drug effects on PPI dependent on estrous cycle stage? And is NT neurotransmission involved in antipsychotic drug effects on PPI in female rats? Thus, specific aim #1 will examine the effects of centrally administered NT on PPI in different stages of the estrous cycle. Specific aim #2 would correlate ovarian hormone regulation of NT release (measured by in vivo microdialysis) with estrous cycle regulation of sensorimotor gating. Specific aim #3 scrutinizes the effects of blockade of neurotensin neurotransmission and antipsychotic drug administration on prepulse inhibition of the acoustic startle response in different phases of the estrous cycle. In addition, it will be determined whether the antipsychotic drug effects are dependent on NT neurotransmission. The demonstration of predicted estrous cycle-related differences in NT release and its association with sensorimotor gating may yield an important clinical correlate and model explaining why female schizophrenia patients in general exhibit a better response to antipsychotic drugs, and why schizophrenic symptoms are exacerbated by low estrogen states.